Combined interventions for the testing and treatment of HIV and schistosomiasis among fishermen in Malawi: a three-arm, cluster-randomised trial

Summary Background Undiagnosed HIV and schistosomiasis are highly prevalent among fishermen in the African Great Lakes region. We aimed to evaluate the efficacy of lakeside interventions integrating services for HIV and male genital schistosomiasis on the prevalence of schistosomiasis, uptake of antiretroviral therapy (ART) for HIV, and voluntary male medical circumcision (VMMC) among fishermen in Malawi. Methods We conducted a three-arm, cluster-randomised trial in 45 lakeshore fishing communities (clusters) in Mangochi, Malawi. Clusters were defined geographically by their home community as the place where fishermen leave their boats (ie, a landing site). Eligible participants were male fishermen (aged ≥18 years) who resided in a cluster. Clusters were randomly allocated (1:1:1) through computer-generated random numbers to either enhanced standard of care (SOC), which offered invitation with information leaflets to a beach clinic offering HIV testing and referral, and presumptive treatment for schistosomiasis with praziquantel; peer education (PE), in which a nominated fisherman was responsible for explaining the study leaflet to promote services to his boat crew; or peer distribution education (PDE), in which the peer educator explained the leaflet and distributed HIV self-test kits to his boat crew. The beach clinic team and fishermen were not masked to intervention allocation; however, investigators were masked until the final analysis. Coprimary composite outcomes were the proportion of participants who had at least one Schistosoma haematobium egg observed on light microscopy from 10 mL of urine filtrate and the proportion who had self-reported initiating ART or scheduling VMMC by day 28. Outcomes were analysed by intention to treat; multiple imputation for missing outcomes was done; random-effect binomial models adjusting for baseline imbalance and clustering were used to compute unadjusted and adjusted risk differences, risk ratios (RRs) and 95% CIs, and intracluster correlation coefficients for each outcome. This trial is registered with ISRCTN, ISRCTN14354324. Findings Between March 1, 2022, and Jan 29, 2023, 45 (65·2%) of 69 clusters assessed for eligibility were enrolled in the trial, with 15 clusters per arm. Of the 6036 fishermen screened at baseline, 5207 (86·3%) were eligible for participation: 1745 (87·6%) of 1991 in the enhanced SOC group, 1687 (81·9%) of 2061 in the PE group, and 1775 (89·5%) of 1984 in the PDE group. Compared with the prevalence of active schistosomiasis in the enhanced SOC group (292 [16·7%] of 1745), 241 (13·6%) of 1775 fishermen in the PDE group (adjusted RR 0·80 [95% CI 0·69–0·94]; p=0·0054) and 263 (15·6%) of 1687 fishermen in the PE group (0·92 [0·79–1·07]; p=0·28) had schistosomiasis at day 28. 230 (13·2%) in the enhanced SOC group, 281 (16·7%) in the PE group, and 215 (12·1%) in the PDE group initiated ART or were scheduled for VMMC. ART initiation or VMMC scheduling was not significantly increased with the PDE intervention (0·88 [0·74–1·05); p=0·15) and was marginally increased with the PE intervention (1·16 [0·99–1·37]; p=0·069) when compared with the enhanced SOC group. No serious adverse events were reported in this trial. Interpretation We found weak evidence for the use of peer education to increase uptake of ART and VMMC, but strong evidence for the added distribution of HIV self-test kits to promote high engagement with services and reduce the prevalence of active schistosomiasis, suggesting a high potential for scale-up in hard-to-reach communities across Malawi. Funding Wellcome Trust and the UK National Institute for Health Research.

A cost-effectiveness analysis was done to estimate the incremental cost per the following trial outcomes: number of fishermen without active schistosomiasis cases or treated, number of fishermen tested for HIV, number of fishermen initiated on ART or VMMC.All costs were expressed in 2022 US dollars.The time horizon for our analysis was 12 months.Due to the main study and time horizon not being more than 1 year, costs and health outcomes were not discounted.Details of the main study's procedures have been reported in the main text and study protocol.

Healthcare resource use and costs
Healthcare resource use by participants were collected at the first beach clinic visit and at day 28 (at follow up).During the first visit the following was collected: receipt of presumptive schistosomiasis treatment (praziquantel), oral HIV self-test kits, serial finger-prick HIV testing, referrals made to ART initiation and continuation of ART, and VMMC booking.At day 28, schistosomiasis testing and presence of active schistosomiasis was recorded.
The identification of inputs used for implementing the beach clinic's services and peer led interventions were obtained through semi structured interviews with key research staff, including those working at the beach clinic (study coordinator, laboratory technician at each clinic, and HTC counsellor at each clinic).Interviews were also conducted with one peer leader per arm.The list was further validated with the study team.
Unit costs of the resources used were obtained from the trial's expenditure documents, consultations with key research and procurement staff of which the study procured resources from.We used international medical prices for the unit cost of medication (praziquental) (Frye,2016).

Activities and materials included in the total costs
The total cost for providing HIV services at the beach clinic comprised of the following: staff time (HTC counsellor and lab technician), cost of conducting unigold and determine HIV tests including the equipment and consumables required, and HIV self-test kits (for intervention arms only).As for VMMC linkage, the costs primarily comprised of personnel costs.
The total cost for providing schistosomiasis related services included: staff time (laboratory technician), the cost of praziquental, and the cost of the equipment and consumables required to conduct schistosomiasis testing.
Overhead costs for the beach clinic such as utility bills, communication costs and cleaning services were apportioned to each beach clinic service equally for simplicity.This was also done for shared capital and other costs such as the beach clinic tents, furniture and shared equipment and consumables across services and the cost of training.Equipment including furniture and infrastructure at the beach clinic were annuitized over their useful life with annual discount rate of 3.5%.With regards to the amount of staff time spent on each activity, the staff were asked during the interviews on how much time they spent conducting each service per day.The respective salaries were then apportioned to each service according to the time spent on each service.
The cost of the peer leaders or the intervention included: the cost of producing the leaflets, the compensation given to the peer leaders per day, and the cost of training.The time spent by the peer leaders on explaining each service was solicited and the cost was apportioned accordingly (for the PE and PDE arms where multiple activities were carried out).The cost of the leaflets and training were divided equally across each beach clinic service.HIVST costs were included in the cost of the peer leaders in the PDE as these were distributed by the peer leaders and was not part of the beach clinic service.
All costs were expressed in 2022 US Dollars.For the costs incurred and obtained from years other than the year 2022, these costs were adjusted using the World Bank GDP deflators (World Bank, 2023).All research specific costs were excluded from this analysis. APPENDIX:

Health outcomes
Health outcomes for the economic evaluation were: number of fishermen without active schistosomiasis or treated for schistosomiasis, number of fishermen tested for HIV, and number of fishermen initiated on ART or VMMC.These outcomes were measured at the first visit to the clinic and at follow up, day 28.

Cost-effectiveness analysis
A cost-effectiveness analysis was conducted from the healthcare provider's perspective.This was done by calculating the incremental cost-effectiveness ratio (ICER).ICERs were therefore calculated by dividing the incremental total costs per arm by the incremental health outcomes observed in the trial.The following health outcomes were used: Number without or treated for schistosomiasis, number of HIV tests conducted, and number of participants linked to VMMC or ART.The primary outcome of the trial is the proportion of active schistosomiasis cases, however for the costing work we have used the number treated for schistosomiasis.This will give the incremental cost to treat or avert an additional schistosomiasis case.To account for the possibility that incremental costs and outcomes may reflect differences in cohort sizes within the study, we calculated the ICERs using a hypothetical cohort size of 2000 for each arm.The relative effect of each intervention found within the study was multiplied by 2000 to get the total numbers per health outcome.For costs, we calculated the total costs for each arm by multiplying arm-specific per person costs by 2000.There is no formal cost-effectiveness threshold for Malawi, regarding this study's outcomes.To the best of our knowledge there has not been similar trials with economic evaluations conducted within a similar population.Therefore, this study will only report the ICERs without relation to a willingness to pay threshold.

Sensitivity analysis
We conducted a probabilistic sensitivity analysis by varying the total cost per arm and the study's outcomes (proportion of fishermen tested for HIV, proportion linked to ART/VMMC, and proportion treated for schistosomiasis).The total costs per arm were varied within their respective gamma distributions, and the outcomes were varied within their respective beta distributions, as estimated from the study's results.This was done by simultaneously drawing 10,000 random samples of costs and outcomes from their distributions to estimate incremental costs and outcomes.The eSOC arm was used as the comparator for this analysis.We then plotted the incremental costs against the incremental outcomes (Figure 2).The incremental cost per additional fisherman treated for schistosomiasis in the PE arm was $11.42 as compared to the eSOC arm.Under the PDE arm, treating schistosomiasis is less costly, and more effective as compared to the eSOC arm, therefore resulting to the PDE arm being dominant.Due to the PE arm being more costly and less effective in testing for HIV, the PE arm was dominated by the eSOC arm.However, the PDE arm dominates the eSOC arm as testing for HIV costs less and is more effective as compared to the eSOC arm.
ART/VMMC linkage delivered under the PE intervention arm is more costly but more effective than the eSOC arm.Under the PDE arm, ART/VMMC linkage is less costly and less effective as compared to the eSOC arm.
The incremental cost per additional fisherman linked to ART/VMMC was -$3.76 and $73.84 in the PE and PDE arms, respectively.
We further compared the PDE arm to the PE arm (Appendix: table 4).The results demonstrated that with regards to schistosomiasis treatment and HIV testing the PDE arm dominates the PE arm.With regards to ART/VMMC linkage, the PDE arm was found to be less costly and less effective as compared to the PE arm.
Figure 2 shows the results of the probabilistic sensitivity analysis.The three graphs plot the incremental total cost of each intervention arm against the incremental outcomes of the study.Therefore, graphs A, B, and C show the incremental total cost of each intervention against the incremental proportion of fishermen tested for HIV, the incremental proportion of fishermen linked to ART/VMMC, and the incremental proportion of fishermen treated for schistosomiasis.For this analysis the eSOC arm was the comparator.Graph A demonstrates that HIV testing under the PE arm is less effective, with little difference in costs compared to the eSOC arm.Under the PDE arm, conducting HIV testing was more effective whilst slightly being less costly.Demonstrating that most estimates under the PDE arm showed dominance over the eSOC arm.Graph B shows that under the PE arm linkage to ART/VMMC is slightly more costly whilst being more effective as compared to the eSOC arm.ART/VMMC linkage under the PDE arm is shown to be less costly whilst being less effective.Shown in graph C, the PE arm is shown to be more effective in treating schistosomiasis whilst being minimally more costly than the eSOC arm.
Treating schistosomiasis under the PDE arm is more effective and less costly than the eSOC arm.The majority of estimates demonstrated that the PDE arm dominates the eSOC arm with regards to treating schistosomiasis. APPENDIX:

APPENDIX: Figure 1 :
Timing of trial activities and follow up APPENDIX:

Table 6 :
Primary and secondary outcomes results using logistic regression ....................OverviewWithin the FISH study, we conducted a cost analysis and economic evaluation to determine the costs and assess whether the two interventions: PE and PDE are cost-effective, in comparison to the eSoc arm in Mangochi, Malawi.A provider perspective was used for this work.

Table 1 :
Unit costs of healthcare resource use items *Capital and equipment costs are given at current purchase price, before annualization.**Consumables used for this activity only included stationary.As stationary was a shared beach clinic cost, it has been included under the shared beach clinic costs of consumables.

Table 2 :
Total costs by trial arm (2022 USD$) Table4, treating schistosomiasis costs more and is more effective under the PE arm.

Table 4 :
Incremental cost effectiveness ratios